title: IL-27 receptor signaling regulates memory CD4+ T cell populations and suppresses rapid inflammatory responses during secondary malaria infection.
abstract: Interleukin-27 (IL-27) is known to control primary CD4(+) T cell responses during a variety of different infections, but its role in regulating memory CD4(+) T responses has not been investigated in any model. In this study, we have examined the functional importance of IL-27 receptor (IL-27R) signaling in regulating the formation and maintenance of memory CD4(+) T cells following malaria infection and in controlling their subsequent reactivation during secondary parasite challenge. We demonstrate that although the primary effector/memory CD4(+) T cell response was greater in IL-27R-deficient (WSX-1(-/-)) mice following Plasmodium berghei NK65 infection than in wild-type (WT) mice, there were no significant differences in the size of the maintained memory CD4(+) T population(s) at 20 weeks postinfection in the spleen, liver, or bone marrow of WSX-1(-/-) mice compared with WT mice. However, the composition of the memory CD4(+) T cell pool was slightly altered in WSX-1(-/-) mice following clearance of primary malaria infection, with elevated numbers of late effector memory CD4(+) T cells in the spleen and liver and increased production of IL-2 in the spleen. Crucially, WSX-1(-/-) mice displayed significantly enhanced parasite control compared with WT mice following rechallenge with homologous malaria parasites. Improved parasite control in WSX-1(-/-) mice during secondary infection was associated with elevated systemic production of multiple inflammatory innate and adaptive cytokines and extremely rapid proliferation of antigen-experienced T cells in the liver. These data are the first to demonstrate that IL-27R signaling plays a role in regulating the magnitude and quality of secondary immune responses during rechallenge infections.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Gwyer Findlay
authors.forename: Ana
authors.initials: A
authors.lastname: Villegas-Mendez
authors.forename: Noelle
authors.initials: N
authors.lastname: O'Regan
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.forename: Lisa-Marie
authors.initials: LM
authors.lastname: Grady
authors.forename: Christiaan J
authors.initials: CJ
authors.lastname: Saris
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Couper
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002452:Cell Count; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology*; D007378:Interleukins / Q000276:immunology* / Q000502:physiology; D008099:Liver / Q000276:immunology; D008288:Malaria / Q000097:blood / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018512:Parasitemia / Q000276:immunology; D010962:Plasmodium berghei; D018123:Receptors, Interleukin / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology
chemical_list: D016207:Cytokines; C486767:Il27 protein, mouse; D007378:Interleukins; D018123:Receptors, Interleukin